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Trial registered on ANZCTR


Registration number
ACTRN12622000538741
Ethics application status
Approved
Date submitted
19/11/2021
Date registered
6/04/2022
Date last updated
15/08/2023
Date data sharing statement initially provided
6/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating two doses of intravenous lidocaine infusion for relief of nerve-related pain that persists after trauma or surgery.
Scientific title
A pilot randomised controlled trial of lidocaine for post-traumatic and post-surgical neuropathic pain: Does dose or patient profile modify the outcome?
Secondary ID [1] 305806 0
Australian and New Zealand College of Anaesthetists, Novice Investigator Grant: N22/ 011
Universal Trial Number (UTN)
U1111-1271-5617
Trial acronym
LIDOPAIN : Lidocaine Infusion Dose Optimisation for Pain After Injury to Nerves
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Peripheral neuropathic pain that persists after trauma or surgery. 323990 0
Condition category
Condition code
Anaesthesiology 321494 321494 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous lidocaine infusion, randomised to either 3 mg/kg, 5 mg/kg delivered in 30-60 min.
The attending unblinded registrar will prepare the dose as informed, cross-checked and recorded by the pharmacist. The blinded doctor and nurse delivering the infusion will chart all information in relation to the delivery. Records from both the preparation and the delivery will be reviewed to confirm fidelity of the intervention when progressing to unblinded reporting of results.
Intervention code [1] 321971 0
Treatment: Drugs
Comparator / control treatment
Placebo control treatment: Intravenous normal saline infusion.
Control group
Placebo

Outcomes
Primary outcome [1] 329538 0
Effective analgesia: Participant-reported and defined as the proportion of participants who report at least 30% reduction in average daily pain on a numerical rating scale at the primary timepoint, relative to baseline average pain (previously recorded seven to ten days prior to infusion).
Timepoint [1] 329538 0
Effective analgesia recorded at 6-8 days post-infusion. This primary outcome is recorded once at this timepoint.
Primary outcome [2] 329988 0
Safety outcome for adverse events: The objective of this outcome is to record the proportion of participants in each dosage group who demonstrate serious adverse events that require ceasing of the infusion and/or contraindicate future lidocaine infusion. Adverse events are recorded in patient charts according to standard procedures at the Tess Cramond Pain and Research Centre, from observations during and after the infusion.

1. Significantly altered level of consciousness: Consciousness will be monitored with verbal contact and physical observation during the infusion to ensure that the patient can
- express mild to moderate symptoms that cause discomfort/unease, and
- communicate symptoms which herald the concerning conditions below (seizures, chest pain or large changes in blood pressure).
Loss of consciousness will be recorded along with treatment (ceasing of the infusion) and response to treatment.

2. Seizures: Records will note
- Nature (type of seizure),
- Duration of the seizure activity, and
- Investigations, treatment and response to treatment.

3. Chest pain reflecting possible cardiac ischemia: records will note
- Nature,
- Location,
- Intensity,
- ECG changes,
- Note whether cardiac arrest/death, and
- Investigations, treatment, and response to treatment.

4. Severe hypertension or hypotension: This will be detected through five-minutely observation of vital signs during the infusion. Records will note
- Mean arterial pressure change of greater than 30 mmHg from baseline or 20 mmHg and the patient reporting symptom associated with hypertension/hypotension.
- Investigations, treatment and response to treatment

In addition to observation by the nurse and doctor during and after infusion to the time of discharge, whether any of the above symptoms are reported to have occurred in the 24 hrs following the infusion will be recorded by
- Follow-up phone-call by the nurse seven days post-infusion, and
- By the researcher at Day 6-8 sensory testing.
Although these will be recorded, adverse events after discharge cannot be more formally assessed.
Timepoint [2] 329988 0
Adverse events recorded from the time of infusion up to 6-8 days post infusion.
Secondary outcome [1] 402986 0
Average daily pain: Participant-recorded daily on a numerical rating scale relative to pre-infusion baseline.
Timepoint [1] 402986 0
Average pain recorded daily up to 12 weeks post-infusion (extends on the primary outcome of average daily pain at 6-8 days post-infusion).
Secondary outcome [2] 402987 0
Current pain: Participant-recorded daily on a numerical rating scale.
Timepoint [2] 402987 0
Current pain recorded daily up to 12 weeks post-infusion.
Secondary outcome [3] 402988 0
Peak pain (worst pain): Participant-recorded daily on a numerical rating scale.
Timepoint [3] 402988 0
Peak pain recorded daily up to 12 weeks post-infusion.
Secondary outcome [4] 402989 0
Number of pain paroxysms in a day: Participant-recorded.
Timepoint [4] 402989 0
Paroxysms recorded daily up to 12 weeks post-infusion.
Secondary outcome [5] 404654 0
The Stanford Expectations of Treatment Scale (SETS): Participant-reported.
Timepoint [5] 404654 0
SETS is recorded once within 7-10 days prior to the lidocaine infusion.
Secondary outcome [6] 404655 0
Brief Pain Inventory (BPI): Participant-reported.
Timepoint [6] 404655 0
BPI
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [7] 404656 0
Depression Anxiety and Stress Scale (DASS-21): Participant-reported.
Timepoint [7] 404656 0
DASS-21
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [8] 404657 0
Pain Catastrophising Scale (PCS): Participant-reported.
Timepoint [8] 404657 0
PCS
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [9] 404658 0
Pain Self-Efficacy Questionnaire (PSEQ): Participant-reported.
Timepoint [9] 404658 0
PSEQ
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [10] 404659 0
Short-form McGill Pain Questionnaire (SF-MPQ-2): Participant-reported.
Timepoint [10] 404659 0
SF-MPQ-2
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [11] 404660 0
Neuropathic pain questionnaire (PainDETECT): Participant-reported.
Timepoint [11] 404660 0
PainDETECT
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [12] 404661 0
Patient-Reported Outcomes Measurement Information questionnaire (PROMIS-29): Participant-reported.
Timepoint [12] 404661 0
PROMIS-29
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [13] 404663 0
Sensory detection thresholds for thermal stimuli, local and remote to the region of neuropathic pain as an indicator for peripheral small fibre function: Laboratory tested by a trained assessor with a thermotest unit.
Timepoint [13] 404663 0
Thermal sensory detection
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [14] 404665 0
Temporal summation local and remote to the region of neuropathic pain as an indicator for pain wind-up; Laboratory tested by a trained assessor with a pin-prick stimulator.
Timepoint [14] 404665 0
Temporal summation
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [15] 404666 0
Pain perception thresholds for thermal and pressure stimuli, local and remote to the region of neuropathic pain, as indicators for peripheral/central sensitisation (especially small fibres for thermal): Laboratory tested by a trained assessor with a thermotest unit and with a pressure algometer.
Timepoint [15] 404666 0
Thermal and pressure pain perception
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [16] 404668 0
Conditioned pain modulation as an indicator for descending inhibition of pain; Laboratory tested by a trained assessor with an ice-bath for conditioned pain and a pressure algometer for the pain perception threshold.
Timepoint [16] 404668 0
Conditioned pain modulation
- Baseline is recorded 7-10 days prior to the lidocaine infusion.
- Second recording at 6-8 days post-infusion.
- Third recording at 80-88 days post-infusion (12 weeks).
Secondary outcome [17] 404670 0
Pharmacokinetic tests: Laboratory tests to identify the peak blood concentrations of lidocaine during the 30min infusion protocol. Four blood samples will be taken at 10min intervals, from five participants in each of the 3mg/kg and the 5mg/kg groups. These data will guide the interpretation of peak concentrations that occur when lidocaine dose is calculated by total body weight, and the validity of the dose-response analyses.
Timepoint [17] 404670 0
Four blood samples for pharmacokinetic tests will be taken at 10min intervals with the 30min lidocaine infusion.

Eligibility
Key inclusion criteria
The inclusion criteria are
- Adults with a documented diagnosis of peripheral neuropathic pain (sensory changes affecting the region of the primary pain as well as qualities identified to be indicative of neuropathic pain in the current short form of the McGill Pain Questionnaire (SF-MPQ-2) and the painDETECT questionnaire.
- Pain for at least 6 weeks duration with moderate to high intensity (average pain at least 5 and worst pain at least 7 on the numerical rating scale) and localised to one side of the body.
- Pain not responsive to other forms of treatment or treatment side effects with oral agents
- Absence of pain affecting the opposite quadrant to the primary site of neuropathic pain. This criterion excludes whole-body pain presentations that are likely to have quite a different combination of dominant pain mechanisms and enables the opposite quadrant to be used as a pain-free remote site for quantitative sensory testing.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The exclusion criteria are
- Inability to understand and respond to instructions and questions in English, or inability to write in English.
- A previous history of a intravenous lidocaine infusion while not under general anaesthetisia, currently receiving lidocaine or its oral analogues (mexiletine or flecainide). Previous intraoperative lidocaine infusion will be noted, but will not be an exclusion criterion.
- Contraindications or precautions for intravenous lidocaine infusion that are included in standard clinical screening for contraindications and precautions for lidocaine administration, as noted on the TGA Product and Consumer Medicine Information Licence for lidocaine:
i) Arrhythmia such as atrial fibrillation, conduction blocks, pacemaker/automatic implantable cardioverter defibrillator, or use of anti-arrhythmic medication. A resting heart rate of under 50 BPM and over 100 BPM.
ii) Moderate to severe cardiac failure, uncontrolled hyper (>170/100) or hypotension (<100/60), severe hepatic, renal, thyroid, diabetes, infections, or haematological conditions. As clinically indicated, the study team will order pathology tests to identify/exclude these conditions.
iii) Seizure disorders that would present a safety risk during infusion or quantitative sensory testing.
iv) Cognitive limitations or psychiatric disorders where the condition is unstable or limiting ability to attend to and to consistently report body perceptions or complete questionnaires (may include schizophrenia, somatization, or acute anxiety), which would contribute increased risk with lidocaine or application of quantitative sensory testing.
v) Pregnancy or breastfeeding.
vi) Allergies, interaction with current medications or abnormal lidocaine sensitivity.
- Health conditions that contraindicate quantitative sensory testing due to increased tissue vulnerability with pressure or thermal stimuli.
- Concomitant neurological conditions that limit peripheral nervous system function in the region of the primary post-trauma pain, or neurological conditions that affect the central nervous system (as moderate traumatic brain injury).
- Body weight >100 kg, as higher weight would require greater than the standard clinical practice maximum dosage of 500mg of lidocaine, to deliver 5mg/kg.
- An electrocardiograph recording will be made to examine for any alterations in trace that would contraindicate lidocaine infusion.
i) This can include a previous ECG within the last 6 months
ii) It can be ordered at the time of screening examination for review later (undertaken at a local facility or at the RBWH).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
For concealment, group allocations will be printed and stored in sealed opaque envelopes with randomisation IDs RAND01-RAND48. These will be provided to the unblinded pharmacist on the day that a participant is attending for their lidocaine infusion, in the sequence of research ID, so that they can prepare allocated infusion dose.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The pharmacist will use the random number generator function in Microsoft excel to generate a randomisation scheme for permuted blocks of 8 participants, with sufficient allocations to cover the study and a drop-out rate up to 20% (RAND01-RAND48).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
This pilot study follows a randomised, parallel, double-blind, placebo control design.
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Categorical variables will be described as frequency and percentage, and continuous variables as mean and standard deviation, or median and interquartile range if not normally distributed.

Primary outcomes will be reported with descriptive statistics:
- Efficacy at reducing pain intensity: Will report the proportion of participants in each group with at least 30% reduction in average pain score relative to their pre-infusion baseline average pain, measured on an 11-point NRS in their daily pain diary at 6-8 days post-infusion.

- Safety outcome: The proportion of participants in each dosage group who demonstrate serious adverse events that require ceasing of the infusion and/or contraindicate future lidocaine infusion, such as severe fatigue, chest pain (non-cardiac), cardiac arrest, seizures, severe hypertension or hypotension during or within 24 hrs of the infusion.
Association between pain reduction with dose, and adverse events with dose, both at the time of infusion and post-infusion, will be examined with Pearson Chi-squared tests.


Secondary outcomes will be analysed with a range of statistical methods:
- Questionnaire results will be reported with descriptive statistics and referenced to normative values.

- Quantitative sensory testing results: To analyse QST continuous data, raw data will be log-transformed (except thermal pain thresholds), and z-scores will be calculated using published normative values for sites (Magerl et al. 2010, DOI: 10.1016/j.pain.2010.07.026). Positive z-scores denote a gain of function, negative z-scores denote a loss of function, and |z| > 1.96 denote values outside of the normative range. Conditioned pain modulation will be quantified as change in pressure pain threshold between baseline and during ice water immersion, whereby conditioned pain modulation is calculated by subtracting the conditioning stimulus pressure pain threshold from the baseline pressure pain threshold, such that negative values reflect nervous system function to achieve pain inhibition (Yarnitsky et al. 2015, DOI: 10.1002/ejp.605). Conditioned pain modulation will be quantified in raw units (kPa) and as a % of baseline pressure pain threshold. Results will be reported as separate z-scores with pressure and with thermal detection, pressure and thermal pain thresholds and temporal summation, to normalise data across body sites to age-stratified and sex-stratified normative values from the German Research Network on Neuropathic pain for prediction of response, and also compared between groups. Quantitative sensory testing data will be compared by an analysis of covariance, with the baseline value and group as main effects.

Patient responses to questionnaires and responses to sensory testing that are associated with a more sustained period of pain relief post-infusion relative to baseline pain, will also be explored with a survival analysis approach. Useful predictors of return to baseline pain post-infusion will be identified using a log-rank test, and Kaplan-Meier estimates univariate analysis. Significant variables will then be used in a Cox regression model with estimated hazards ratios and 95% confidence intervals.

Pharmacokinetic analysis will be reported with descriptive statistics.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
5/12/2022
Actual
6/12/2022
Date of last participant enrolment
Anticipated
28/06/2023
Actual
21/06/2023
Date of last data collection
Anticipated
27/09/2023
Actual
21/06/2023
Sample size
Target
40
Accrual to date
Final
8
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 21099 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 35955 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 309936 0
Charities/Societies/Foundations
Name [1] 309936 0
Australian and New Zealand College of Anaesthetists - Novice Investigator Grant
Country [1] 309936 0
Australia
Funding source category [2] 310156 0
Hospital
Name [2] 310156 0
Royal Brisbane and Women's Hospital
Country [2] 310156 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane and Women's Hospital
Address
Tess Cramond Pain and Research Centre
Critical Care and Clinical Support Services
Royal Brisbane and Women's Hospital
Butterfield St,
Herston, Queensland, 4029
Country
Australia
Secondary sponsor category [1] 311240 0
None
Name [1] 311240 0
Address [1] 311240 0
Country [1] 311240 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309655 0
Royal Brisbane and Women's Hospital, Human Research Ethics Committee
Ethics committee address [1] 309655 0
Ethics committee country [1] 309655 0
Australia
Date submitted for ethics approval [1] 309655 0
05/10/2021
Approval date [1] 309655 0
10/11/2021
Ethics approval number [1] 309655 0
HREC/2021/QRBW/79516

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114922 0
Dr Gunjeet Minhas
Address 114922 0
Tess Cramond Pain and Research Centre
Royal Brisbane and Women's Hospital
Butterfield St
Herston, Queensland 4029
Country 114922 0
Australia
Phone 114922 0
+61 7 36368111
Fax 114922 0
Email 114922 0
Gunjeet.Minhas@health.qld.gov.au
Contact person for public queries
Name 114923 0
Andrew Claus
Address 114923 0
Tess Cramond Pain and Research Centre
Royal Brisbane and Women's Hospital
Butterfield St
Herston, Queensland 4029
Country 114923 0
Australia
Phone 114923 0
+61 7 3647 6961
Fax 114923 0
Email 114923 0
Andrew.Claus@health.qld.gov.au
Contact person for scientific queries
Name 114924 0
Andrew Claus
Address 114924 0
Tess Cramond Pain and Research Centre
Royal Brisbane and Women's Hospital
Butterfield St
Herston, Queensland 4029
Country 114924 0
Australia
Phone 114924 0
+61 7 3647 6961
Fax 114924 0
Email 114924 0
Andrew.Claus@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Participant presentations will be unique and risk being re-identifiable from breadth of profile data obtained. For this reason the protocol approved by the Human Research Ethics committee notes that: "All data obtained in the course of research data collection sessions, the pain diary and lidocaine infusion will remain confidential and used only for the purpose of this research project...Re-identifiable data will be stored either in folders (for paper records) or put onto a secure computer server, which can only be accessed by the researchers."


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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